DESCRIPTION (Adapted from applicant's description): The candidate's long term goal is a career as a physician/scientist in immunodeficiency research and clinical practice. He will use the Mentored Clinical Scientist Development Award for a period of intense training in basic science, which will allow him to become an independent basic science investigator. The mentor's laboratory in the Jonsson Cancer Center at UCLA and the candidate's position as a clinical instructor of the Division of Allergy/Immunology/Rheumatology, Dept. of Pediatrics, UCLA School of Medicine, provide an excellent environment for this transition in the candidate's career. The goal of the proposed project is to identify ligands for the SH2 domain of the non-receptor tyrosine kinase Btk. The primary human immunodeficiency, X-linked agammaglobulinemia (XLA), leads to a block in normal B cell development and results from mutations in the gene encoding Btk. A hallmark of the disease is a nearly total lack of peripheral B cells and plasma cells, resulting in a profound lack of antibodies in affected boys. Btk, and in particular the Btk-SH2 domain are required for B cell receptor (BCR)-induced sustained Ca2+ signals in B cells. These calcium signals are critical for the transcriptional events regulating normal B cell development and activation. The proposed studies will test the hypothesis that a phosphorylated protein binding to Btk-SH2 is a critical linker of Btk to sustained Ca2+ signals. The investigators propose to identify this ligand using both biased (analysis of known candidate adaptor proteins) and unbiased (a yeast three-hybrid cloning strategy) approaches.